Current treatments to prevent allograft rejection while quite effective are nevertheless costly, associated with significant systemic toxicity, and indiscriminately impair immune system function so that transplant recipients are at increased risk for a variety of infectious illnesses and cancers. Furthermore, traditional immunosuppressive therapies have proven unable to prevent the rejection of potentially curative islet transplants in individuals with insulin dependent diabetes mellitus (IDDM). Rodent and non-human primate model studies have suggested that anti-CD154 (CD40L) antibody-based treatments, alone or in combination with other immune system modulators may significantly improve the approach to patients requiring health sustaining allo-transplants. Preliminary data suggests that this therapy may more specifically impair the anti-graft immune response, can be administered intermittently, and may be associated with less toxicity. Our overall goal is to develop this novel therapy for clinical application. We will study highly relevant non-human primate islet and kidney allograft models, transitioning into clinical trials as warranted by preclinical studies. Among the several critical questions to be addressed: (1) what is the immunological mechanism underlying the prevention of allograft rejection?. (2) are anti-CD154-based therapies safe and effective when co-administered with "traditional" immunosuppressive agents including calcineurin phosphatase inhibitors, glucocorticoids, and/or mycophenolate mofetil?. (3) is the efficacy of anti-CD154-based therapies enhanced by increasing the donor antigen load in the form of co-administered donor-specific bone marrow? (4) is the efficacy of anti-CD154-based therapies enhanced by agents that interfere with the B7 receptors (CD80 and CD86) ability to interact with their counter-receptors and CTLA4 (CD152)? (5) how specific is the immune inhibition? (6) will anti-CD154-based therapy reverse and/or decrease the incidence of chronic rejection?. (7) can rejection episodes occurring following induction therapy with anti-CD154 can be safely rescued?. and (8) are anti-CD154 antibody mediated effects the result of blocking CD154's interaction with CD40?. direct effects on cells expressing CD154?. or both?